Prostate cancer (PCa) is a prevailing disease found in African American men, and is the most frequently diagnosed cancer in American men. African American males died of PCa in a 2.39-folder higher rate as compared with Caucasian males, while the average death rate due to all cancers was only 1.34-fold higher between these two races (Cancer Statistics 2010)^. Surgery, radiation therapy and androgen-deprivation therapy have been developed and applied widely to control PCa; however, prostate cancer patients still died of Castration Resistant Prostate Cancer (CRPC). Molecular signaling pathways contributing to the initiation and progression of PCa; particularly, the mechanism of CRPC growth remain to be elucidated in order to develop efficient strategies for cancer control. Aberrant regulation of Pten-PI3K-Akt pathway, p53 loss and Skp2 activation are commonly found in CRPC. Further investigation on their roles in PCa progression will help us to understand the incidence and mortality rate of PCa, and the disparities among ethnic and racial groups.